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Publication year
2015Source
American Journal of Respiratory and Critical Care Medicine, 191, 10, (2015), pp. 1126-38ISSN
Publication type
Article / Letter to editor
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Organization
Pulmonary Diseases
Intensive Care
Journal title
American Journal of Respiratory and Critical Care Medicine
Volume
vol. 191
Issue
iss. 10
Page start
p. 1126
Page end
p. 38
Subject
Radboudumc 0: Other Research RIHS: Radboud Institute for Health Sciences; Radboudumc 3: Disorders of movement DCMN: Donders Center for Medical NeuroscienceAbstract
RATIONALE: The clinical significance of diaphragm weakness in critically ill patients is evident: it prolongs ventilator dependency, and increases morbidity and duration of hospital stay. To date, the nature of diaphragm weakness and its underlying pathophysiologic mechanisms are poorly understood. OBJECTIVES: We hypothesized that diaphragm muscle fibers of mechanically ventilated critically ill patients display atrophy and contractile weakness, and that the ubiquitin-proteasome pathway is activated in the diaphragm. METHODS: We obtained diaphragm muscle biopsies from 22 critically ill patients who received mechanical ventilation before surgery and compared these with biopsies obtained from patients during thoracic surgery for resection of a suspected early lung malignancy (control subjects). In a proof-of-concept study in a muscle-specific ring finger protein-1 (MuRF-1) knockout mouse model, we evaluated the role of the ubiquitin-proteasome pathway in the development of contractile weakness during mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: Both slow- and fast-twitch diaphragm muscle fibers of critically ill patients had approximately 25% smaller cross-sectional area, and had contractile force reduced by half or more. Markers of the ubiquitin-proteasome pathway were significantly up-regulated in the diaphragm of critically ill patients. Finally, MuRF-1 knockout mice were protected against the development of diaphragm contractile weakness during mechanical ventilation. CONCLUSIONS: These findings show that diaphragm muscle fibers of critically ill patients display atrophy and severe contractile weakness, and in the diaphragm of critically ill patients the ubiquitin-proteasome pathway is activated. This study provides rationale for the development of treatment strategies that target the contractility of diaphragm fibers to facilitate weaning.
This item appears in the following Collection(s)
- Academic publications [245050]
- Electronic publications [132309]
- Faculty of Medical Sciences [93209]
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